Journal article
Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC
VIRUSES-BASEL, v 15(5), 1185
17 May 2023
PMID: 37243271
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp(368) Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the a-carboxylic acid group of Asp(368), opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.
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Details
- Title
- Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC
- Publication Details
- VIRUSES-BASEL, v 15(5), 1185
- Publisher
- MDPI; BASEL
- Grant note
- This work was supported by P01-GM56550/AI150741 to A.B.S., C.A., and A.F. This study was also supported by a Canadian Institutes of Health Research (CIHR) foundation grant #352417 to A.F. Funds were also provided by a CIHR team grant #422148 to A.F., a Canada Foundation for Innovation (CFI) grant #41027 to A.F., and by the National Institutes of Health to A.F. (R01 AI148379 and R01 AI150322), to M.P. and A.F. (R01 AI129769) and M.P. (AI116274), and (AI120756) to M.P. and Georgia Tomaras. This work was partially supported by 1UM1AI164562-01; co-funded by the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Neurological Disorders and Stroke; the National Institute on Drug Abuse; and the National Institute of Allergy and Infectious Diseases to A.F. A.F. is the recipient of a Canada Research Chair on Retroviral Entry #RCHS0235 950-232424. The funders had no role in the study's design, in the data collection and analysis, in the decision to publish, or in the preparation of the manuscript.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:000997248800001
- Scopus ID
- 2-s2.0-85160622266
- Other Identifier
- 991021860619004721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology